Method for producing cephalosporins

ABSTRACT

A method for producing cephalosporins 7-substituted with an amino-thiazolylacetic group by reacting 7-ACA or its derivatives having the amino group and the carboxyl protected with reactive derivatives of amino-thiazolylacetic acid.

FIELD OF THE INVENTION

[0001] The present invention relates to a method for producingcephalosporins 7-substituted with an amino-thiazolylacetic group offormula

[0002] in which R₁ is hydrogen or a residue of a nucleophilic compound,R₂ is a hydroxyl or substituted hydroxyl, R₃ is hydrogen or methoxyl.

[0003] U.S. Pat. No. 5,567,813 describes a method for producingcephalosporins of formula (I)—in which however R₃ is onlyhydrogen—according to which an acyl group of formula

[0004] is introduced into the amino group of molecules of formula

[0005] by reacting a compound of formula (V) with a compound of formula

[0006] where R₄ is a C₁-C₄ alkyl.

BACKGROUND OF THE INVENTION

[0007] The alkyl groups (II) and their preparation are described in U.S.Pat. No. 4,152,432 and U.S. Pat. No. 4,327,210; the preparation of thecompounds of formula (IV) is described in U.S. Pat. No. 5,502,200 in thename of the same proprietor as U.S. Pat. No. 5,567,813.

DISCUSSION OF THE RELATED ART

[0008] According to U.S. Pat. No. 5,567,813, the compound (IV) isreacted with the compound (V) in which the reactive groups NH₂ and COOHare free: it has been noted that for certain meanings of R₁, the methoddescribed in the US patent leads to the production of cephalosporins (I)with high yields and purities, whereas for other meanings of R₁, to givecertain important cephalosporins such as cefpirome (Examples 13 and 14)and cefepime (Examples 15 and 16), the yields are decidedly lower.

BRIEF SUMMARY OF THE INVENTION

[0009] The object of the present invention is to provide a process whichcan be easily implemented to produce all cephalosporins of formula (I)with the same ease and with high yields.

DETAILED DESCRIPTION OF THE INVENTION

[0010] This process is characterised by introducing an acyl group offormula

[0011] into the amino group of a molecule of formula

[0012] by reacting in an anhydrous organic solvent a compound of formula(III) with a compound of formula

[0013] where R₄ is a C₁-C₄ alkyl, finally removing the trimethylsilylgroups by known methods, to give the cephalosporins of formula (I).

[0014] Preferably said residue of a nucleophilic compound is chosen fromthe group consisting of methoxy, acetoxy,(1-methyl-1H-tetrazol-5-yl)thio,(5-carboxymethyl-4-methyl-2-thiazolyl)thio, (2-furanylcarbonyl) thio,(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl)thio,1-methylpyrrolidine, 2,3-cyclopentene-1-pyridine,1-(5,6,7,8-tetra-hydroquinoline) and 1-pyridine, said substitutedhydroxyl being chosen from the group consisting of methoxyl and1-carboxy-1-methylethoxy.

[0015] Again preferably, said inert anhydrous organic solvent is chosenfrom the group consisting of methylene chloride, ethylacetate and DMF.

[0016] The compounds of formula (III) are easily obtained from moleculesof formula (V) in the manner described in detail in EP-B-0612750. Someembodiments of the invention will now be described in detail.

EXAMPLE 1

[0017] 10 g of7-amino-3-(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid are suspended in 70 ml of dichloromethane. 18.4 g ofN,O-bis-(trimethylsilyl)acetamide are added and the mixture is agitatedfor 2 h at ambient temperature.

[0018] 16.2 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 4 hours.30 ml of water are added to the reaction mixture and 30% NaOH is drippedin at 15°/20° C. until pH 7.5-7.8 is attained.

[0019] The aqueous phase is separated and is treated for 20 minutes atambient temperature with 1 g of carbon, then filtered and washed with 15ml of water. 60 ml of acetone and 3 2 g of NaCl are added.Crystallization commences and the mixture is left under agitation for 1h.

[0020] 240 ml of acetone are finally dripped in to complete theprecipitation. The mixture is filtered, washed with 20 ml of 9:1acetone/water and then with 400 ml of acetone.

[0021] It is dried at +40° C. under reduced pressure.

[0022] 16.8 g of ceftriaxone disodium hemiheptahydrate are obtained(titre 84% as anhydrous acid). Molar yield: 94.6%.

[0023] Ceftriaxone is a compound of formula (I) in which R₁ is(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio, R₂ ismethoxyl and R₃ is hydrogen.

EXAMPLE 2

[0024] 10 g of7-amino-3-(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid are suspended in 50 ml of anhydrous DMF. 18.4 g ofN,O-bis-(trimethylsilyl)acetamide are added and the mixture is agitatedfor 2 h at ambient temperature.

[0025] 16.2 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 4 hours.30 ml of water are added to the reaction mixture and 30% NaOH is drippedin at +15/+20° C. until pH 7.5-7.8 is attained.

[0026] The aqueous solution is washed repeatedly with dichloromethane.

[0027] The resultant aqueous solution is treated for 20 minutes atambient temperature with 1 g of carbon, then filtered and washed with 15ml of water. 250 ml of acetone are rapidly added and the mixture is leftunder agitation to crystallize for 1 h.

[0028] The mixture is filtered, washed with 20 ml of 9:1 acetone/waterand then with 400 ml of acetone.

[0029] It is dried at +40° C. under reduced pressure.

[0030] 16 g of ceftriaxone disodium hemiheptahydrate are obtained (titre82% as anhydrous acid).

EXAMPLE 3

[0031] 10 g of7-amino-3-(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid are suspended in 70 ml of dichloromethane. 5.9 g oftrimethylchlorosilane and 8.7 g of hexamethyldisilazane are added. Themixture is agitated for 2 h at ambient temperature.

[0032] 16.2 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 18 hours.

[0033] Operating as in Example 1 results are obtained which arequantitatively perfectly superimposable.

EXAMPLE 4

[0034] 10 g of7-amino-3-(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid are suspended in 70 ml of dichloromethane. 16.7 g ofN,N′-bis-trimethyl-silylurea are added and the mixture is agitated for 2h at ambient temperature.

[0035] 16.2 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for about 10hours.

[0036] 30 ml of water are added to the reaction mixture and 30% NaOH isdripped in at +15°/20° C. until pH 7.5-7.8 is attained.

[0037] The aqueous phase is separated and is treated for 20 minutes atambient temperature with 1 g of carbon, then filtered and washed with 15ml of water. 60 ml of acetone are added. Crystallization commences andthe mixture is left under agitation for 1 h.

[0038] 240 ml of acetone are finally dripped in to complete thecrystallization. The mixture is filtered, washed with 20 ml of 9:1acetone/water and then with 400 ml of acetone.

[0039] It is dried at +40° C. under reduced pressure.

[0040] 16.7 g of ceftriaxone disodium hemiheptahydrate are obtained(titre 83% as anhydrous acid).

EXAMPLE 5

[0041] 10 g of 7-aminocephalosporanic acid are suspended in 70 ml ofdichloromethane. 7.9 g of N,O-bis-(trimethylsilyl)acetamide are addedand the mixture is agitated for 1 h at ambient temperature.

[0042] 8.1 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 8 hours.

[0043] On termination of the reaction the synthesis mixture is drippedinto 80 ml of water at +15/+20° C., adjusting the pH to 7.5-7.8 with 15%NaOH during the dripping.

[0044] The aqueous phase is separated, diluted with 16 ml of isopropylalcohol and then with water to a total of 195 ml. 5 ml of ethyl acetateare added to the solution obtained, it is cooled to 0° C. and 15% HCladded until pH 3.5 is achieved, where the first crystals appear. Themixture is agitated for 30 min and the pH then lowered to 2.7. It isagain agitated for 30 min and filtered, washing with acetone.

[0045] It is dried at +40° C. under reduced pressure.

[0046] 8.5 g of cefotaxime acid are obtained.

[0047] Molar yield: 94.4%.

[0048] Cefotaxime is a compound of formula (I) in which R₁ is acetoxy,R₂ is methoxyl and R₃ is hydrogen.

EXAMPLE 6

[0049] 5.0 g of 7-aminocephalosporanic acid are suspended in 35 ml ofanhydrous DMF.

[0050] 7.3 g of N,O-bis-(trimethylsilyl)acetamide are added whilemaintaining the temperature at +20°/+25° C. The 7-aminocephalosporanicacid dissolves rapidly and totally.

[0051] 7.5 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 18 hours.On termination of the reaction 65 ml of water and 65 ml of methylenechloride are added.

[0052] The mixture is adjusted to pH 7 with NaHCO₃ and the phases areseparated. The aqueous phase is washed repeatedly with dichloromethane.

[0053] 6 ml of isopropyl alcohol are added to the aqueous phase and thendiluted to a total of 195 ml with water. 5 ml of ethyl acetate are addedto the solution obtained, it is cooled to 0° C. and 15% HCl added untilpH 3.5 is achieved, where the first crystals appear. The mixture isagitated for 30 min and the pH then lowered to 2.7.

[0054] It is again agitated for 30 min and filtered, washing withacetone.

[0055] It is dried at +40° C. under reduced pressure.

[0056] 7.7 g of cefotaxime acid are obtained.

[0057] Molar yield: 93.5%.

EXAMPLE 7

[0058] 10 g of7-amino-3-[(1-methyl-1-pyrrolidine)methyl]-3-cephem-4-hydroiodide areadded to 300 ml of dichloromethane in a nitrogen atmosphere.Trimethylchlorosilane (4.7 ml) and hexamethyl disilazane (7.7 ml) areadded, the temperature is adjusted to 25°/30° C. and the mixture isagitated for 2 hours, again at 25°/30° C. The mixture is cooled to 20°C., 11.5 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded, and the mixture left under agitation at 20°/+25° C. overnight.The reaction mixture is added slowly to water (50 ml) and after 60minutes of agitation the phases are separated. The aqueous phase iswashed with dichloromethane and 6N hydrochloric acid and acetone (100ml) are added to the aqueous phase. The mixture is left to crystallizefor 30 minutes and further acetone (180 ml) are then added to completethe crystallization. After 60 minutes of agitation the mixture isfiltered, washed with acetone and dried at 40° C. 12.2 g of cefepimedihydrochloride monohydrate are obtained.

[0059] Molar yield: 94.8%.

EXAMPLE 8

[0060] 5 g of7-amino-3-(2-furanylcarbonyl)thiomethyl-3-cephem-4-carboxylic acid aresuspended in 35 ml of dichloromethane. 5.5 g ofN,O-bis-(trimethylsilyl)acetamide are added and the mixture is agitatedfor 3 h at ambient temperature.

[0061] 6.4 g ofdiethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate areadded and the mixture left to react at ambient temperature for 6 hours.

[0062] 50 ml of water are added to the solution at the end of thereaction and 30% NaOH is dripped in until pH 7.5 is attained. Theaqueous phase is separated and decolorized with 1 g of carbon for 20min.

[0063] After filtration 50 ml of 36% HCl are slowly dripped in until pH3 is attained. The organic phase is separated, 3.5 g of sodium2-ethylhexanoate are added and the mixture left to crystallize at 0° C.for 8 h, then filtered, washing with cold tetrahydrofuran.

[0064] It is dried at +30° C. under reduced pressure.

[0065] 9.2 g of ceftiofur sodium salt are obtained.

[0066] Molar yield: 90%

[0067] Proceeding in the same manner as the aforedescribed Examples, butusing reagents of formula (III) in which R₁ is chosen from the groupconsisting of methoxy, (1-methyl-1H-tetrazol-yl)thio,(5-carboxymethyl-4-methyl-2-thiazolyl)thio, 2,3-cyclopentene-1-pyridine, 1-(5,6,7,8-tetrahydro-quinoline) and1-pyridine, and R₂ is chosen from the group consisting of methoxy and1-carboxy-1-methylethoxy, other important cephalosporins are obtained,known by the name of cefmenoxime, cefodizime, cefpirome, cefpodoxime(from which cefpodoxime proxethyl can be prepared), cefquinome andceftazidime.

What we claim is:
 1. A method for producing cephalosporins 7-substitutedwith an amino-thiazolylacetic group of formula

in which R₁ is hydrogen or a residue of a nucleophilic compound, R₂ is ahydroxyl or substituted hydroxyl, R₃ is hydrogen or methoxyl, wherein anacyl group of formula

is introduced into the amino group of a molecule of formula

by reacting in an anhydrous organic solvent a compound of formula (III)with a compound of formula

where R₄ is a C₁-C₄ alkyl, finally removing the trimethylsilyl groups byknown methods, to give the cephalosporins of formula (I).
 2. A method asclaimed in claim 1, wherein said residue of a nucleophilic compound ischosen from the group consisting of methoxy, acetoxy,(1-methyl-1H-tetrazol-5-yl)thio,(5-carboxymethyl-4-methyl-2-thiazolyl)thio, (2-furanylcarbonyl)thio,(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio,1-methyl-pyrrolidine, 2,3-cyclopentene-1-pyridine,1-(5,6,7,8-tetrahydro-quinoline) and 1-pyridine, said substitutedhydroxyl being chosen from the group consisting of methoxy and1-carboxy-1-methylethoxy.
 3. A method as claimed in claims 1 whereinsaid inert anhydrous organic solvent is chosen from the group consistingof methylene chloride, ethylacetate and DMF.
 4. A method as cliamed inclaim 2 wherein said inert anhydrous organic solvent is chosen from thegroup consisting of methylene chloride, ethylacetate and DMF.